Case 4 -

Sertoli Cell Tumor of the Right Ovary Esther Oliva Massachusetts General Hospital Boston, Massachusetts

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Clinical History: A 68-year old woman, status post-hysterectomy, was found to have a pelvic mass. Bilateral oophorectomy was performed. Diagnosis: Sertoli cell tumor of the right ovary Case 4 - Figure 1 - Compact and spindle nests of tumor cells associated with scant fibromatous stroma. The cells have moderate amounts of eosinophilic cytoplasm and uniform oval to spindled nuclei. Case 4 - Figure 2 - The tumor contains scattered "endometrioid-type glands" admixed with predominantly solid tubules and some hollow tubules. Case 4 - Figure 3 - Small solid tubules with abundant clear cytoplasm surrounded by abundant fibromatous stroma. Notice the absence of Leydig cells. Case 4 - Figure 4 - Well-formed, elongated solid tubules with elongated, very focally grooved nuclei associated with some mitotic activity. Gross and microscopic examination: The right ovary measured 13 x 13 x 8 cm and was multilobulated with a smooth outer surface. Sectioning revealed a homogenous-solid, yellow tan cut surface. The opposite ovary measured 4 x 3.3 x 1.4 cm and was grossly unremarkable. In some areas, the tumor was composed of compact nests, cords and solid tubules, the latter showing focally dilated "glandular-like" spaces, separated by thin strands of fibrous tissue imparting a vague and irregular lobular architecture. On higher magnification the cells were mostly spindled-shaped, with scant to relatively abundant clear or eosinophilic cytoplasm. There was mild to moderate cytologic atypia with a relatively brisk mitotic activity, the highest count being 6 mitosis per 10 high power fields. In other areas, the tumor contained solid tubules ans scattered hollow tubules with an appearance similar to that seen in immature prepuberal testis; those were separated by abundant fibromatous stroma. The cells had abundant pale vacuolated cytoplasm and bland nuclear features. No necrosis was seen. After very extensive sampling of the tumor no Leydig cells were identified. Immunohistochemical findings: The tumor cells were extensively positive for inhibin. They were also positive for keratin, CD99, calretinin, and only scattered cells stained for Muscle Actin. EMA, Chromogranin, S-100 and NSE were negative. Discussion: Sertoli cell tumors are defined as neoplasms composed of hollow or solid tubules separated by variable amounts of stroma containing only rare or no Leydig cells. These tumors account for approximately 4% of Sertoli-stromal cell tumors, and they occur at any age (mean, 30 years). They are commonly non-functioning, but if functioning they are more frequently estrogenic, although they may show evidence of androgen or rarely progesterone production 1-5. Rare tumors, most of them of the lipid-rich type have resulted in isosexual precocity. Occasionally Sertoli cell tumors have been associated with renine production 6, or have been associated with the Peutz-Jeghers syndrome 5,7,8. On gross examination Sertoli cell tumors are typically unilateral, and they average 9 cm in largest dimension. They are lobulated, with a solid, and yellow or brown cut surface. On microscopic examination, all Sertoli cell tumors have at least a focal tubular component, the tubules being hollow or solid, and round or elongated. The solid tubules may simulate prepubertal testicular tubules, as it was focally seen in this case, or atrophic tubules of the adult testis. The tubules are lined by cuboidal to columnar cells that have moderate to abundant cytoplasm that may be eosinophilic or pale and vaculated. The solid tubules often contain large cells with abundant cytoplasmic lipid (lipid-rich Sertoli cell tumor). This tumor was originally thought to be a form of granulosa cell tumor and was called "folliculome lipidique". This tubular growth is the commonest and the predominant pattern in half of these tumors. Other patterns that can be seen and may be quite striking include cord-like and diffuse. This cord-like pattern was very prominent in this case. Other growth patterns are rare. Most of the tumors are composed of cells that show minimal nuclear atypia, some may contain cells with scattered bizarre nuclei as those seen more often in granulosa cell tumors 9 and the mitotic rate is typically low. Although nuclear grooves were originally described in the Sertoli cells of normal testes, they are found only occasionally in its tubules. The stroma is typically fibromatous, forming bands that separate lobules of Sertoli tubules, but may show marked sclerosis as it has been reported in some testicular Sertoli cell tumors 10. Sertoli cell tumors are frequently positive for fat. The immunohistochemical profile of these tumors shows that they are typically vimentin and keratin positive but EMA negative 11,12, although focal EMA positivity has been reported in rare Sertoli cell tumors 11,13. They are typically positive for inhibin 14,15. In our experience, inhibin is a good marker for Sertoli cell tumors and in our most recent study 18/22 Sertoli cell tumors were inhibin positive including one composed of oxyphilic cells 16. Most other series have also found a high percentage of inhibin positivity for these tumors 17-21. They are also frequently positive for CD99. McCluggage et al., were the first ones to show CD99 positivity in ovarian granulosa cell tumors 22. Sertoli cell tumors have recently shown to be positive for calretinin. Some authors consider calretinin positivity in sex-cord stromal tumors more sensitive although less specific than inhibin staining 23,24. These tumors can also occasionally be positive for smooth muscle actin and S-100 16. CD10, an antibody mainly used in gynecological pathology in the differential diagnosis of smooth muscle tumors and endometrial stromal tumors also stains sex-cord stromal tumors including Sertoli cell tumors 25. From a practical point of view probably the most useful panel of antibodies includes EMA, inhibin and calretinin. Electronmicroscopic studies have shown that the tumor cells have tight junctions and desmosomes as well as abundant rough endoplasmic reticulum and lipid 2,26,27. Some contain non-crystalline parallel arrays of Charcot-Böttcher microfilaments. It is important to remember that Sertoli cell tumors are rare and when they may show an unusual growth pattern as in the case presented here, these tumors may be confused with: 1. Endometrioid carcinoma: It is well known that endometrioid carcinomas (ECs) may have a sex-cord-like appearance 29 but even more specifically they may have histologic features that resemble those of Sertoli cell tumors containing cords and tubules (Sertoliform EC) 30,31 as the case presented here. The stroma is also frequently fibromatous and some cases may contain small clusters or isolated cells consistent with luteinized stromal cells surrounding the epithelial elements. Typical areas of EC are almost always present merging with the sertoli-like areas, often with squamous metaplasia, mucinous metaplasia or even a background of adenofibroma. Other ECs are composed of cells with abundant eosinophilic cytoplasm mimicking Sertoli cell tumor, oxyphilic type 8. Finally some ECs may have a predominant spindle cell component and those can also raise the differential diagnosis with a Sertoli cell tumor with a spindle appearance as shown in the case discussed here 32. The vast majority of ECs are inhibin negative cells including those with sex-cord like features 33, but in contrast to Sertoli cell tumors they are typically EMA positive. Finally CK7 has been shown to be positive in ovarian ECs including those with sertoliform appearance. Ovarian sex-cord stromal tumors tested for CK7 including granulosa cell tumors, SLCTs, and sex-cord tumors with annular tubules are negative for this antibody although there is very limited experience 34,35. Estrogen and progesterone receptors on the other hand are not useful. 2. Wolffian tumor of probable adnexal origin (FATPWO): Although more frequently seen in the broad ligament, these tumors may grow predominantly in the ovary and they may form pseudotubular structures with cells that have a cytologic appearance that slightly overlaps with that seen in Sertoli cell tumors. Typically, however, they are characterized by an admixture of other patterns, including slit-like and solid areas composed of small oval or spindle-shaped cells, which are not characteristic of Sertoli cell tumors 36. In rare cases the differential diagnosis may be extremely difficult. Although FATPWO may be positive for inhibin, the staining is usually weak and focal 20,37. These tumors may be positive or negative for calretinin 38+23 and CD99 although the experience with these antibodies in these tumors is very limited. CD10 has been reported to be very useful in tumors of mesonephric derivation 39 but in our limited experience CD10 can also be positive in sex-cord stromal tumors including Sertoli cell tumors 16. 3 . Carcinoid tumor: These neoplasms are rarely in the differential diagnosis of Sertoli cell tumors, but on occasion they may be predominantly composed of cords and trabeculae resembling to some extent the focal cord-like pattern seen in Sertoli cell tumors. However, the ribbons of carcinoid tumors are typically longer and thicker and the stroma is less cellular and frequently more extensively fibrotic than in Sertoli cell tumors. Moreover, other areas show a more characteristic insular growth pattern. Approximately 70% of carcinoids are associated with a teratomatous component. They are positive for Grimelius or Fontana-Masson and chromogranin and negative for inhibin. 4. Well-differentiated Sertoli Leydig cell tumor: These neoplasms are characterized by the presence of abundant Leydig cells in between the lobules of Sertoli cell tubules. The presence of Leydig cells should raise high suspicion for a Sertoli Leydig cell tumor 28. For this reason extensive sampling is very important in these cases. The presence of heterologous components also strongly supports the diagnosis of Sertoli-Leydig cell tumor 1. 5. Metastatic tumors to the ovary: Some tubular Krukenberg tumors with a luteinized stroma and estrogenic manifestations may rarely be confused with Sertoli cell tumors. The presence of an extraovarian primary tumor, usually bilateral ovarian involvement, spread of tumor elsewhere in the abdomen and typical microscopic features including the presence of signet-ring cells, which stain positively for mucin, and some degree of cytologic atypia strongly establish a diagnosis of a Krukenburg tumor. 6. Oxyphilic tumors: The oxyphilic variant of Sertoli cell tumor should be distinguished from other oxyphilic tumors involving the ovary including endometrioid carcinoma, clear cell carcinoma, hepatoid carcinoma, luteinized granulosa cell tumor, steroid cell tumor, and metastatic malignant melanoma. Among those, steroid cell tumors are the ones that most often have cells with abundant eosinophilic cytoplasm. Although they typically have a diffuse pattern of growth, they may have a nesting pattern mimicking solid tubule formation. Unlike oxyphilic Sertoli cell tumors, they have centrally located nuclei and many of the cells contain fat vacuoles visible on microscopic examination. Steroid cell tumors are usually androgenic, inhibin positive but keratin negative, and they are not associated to the Peutz-Jeghers syndrome. The prognosis of Sertoli cell tumors is generally good and related to tumor stage and degree of differentiation. In one of the largest series reported by Tavassoli and Norris, 2 tumors (7%) recurred after initial surgery. Those cases showed stromal infiltration by single tumor cells, but only the patient with a tumor that showed adhesions to the pelvic structures had a fatal course 2. In the series by Young and Scully, one patient died after one year of follow-up even though the tumor was confined to the ovary, but it contained poorly differentiated areas 1. 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